Synthesis of 18F-labeled tracers in hydrous organic solvents

ABSTRACT

A method for synthesizing an  18 F-labeled probe. The method includes a step of eluting an amount of  18 F with a first solvent which includes a predetermined amount of water and at least one organic solvent. In this step, the  18 F elutes as an  18 F solution. The method also includes a step of using the  18 F solution to perform  18 F-labeling in the presence of at least one labeling reagent and at least one phase transfer catalyst so as to generate the  18 F-labeled probe. In the method, there is no step of drying the  18 F starting from a time when the eluting step is performed and ending at a time when the  18 F-labeling step is performed.

This application is the U.S. national phase application of PCTInternational Application No. PCT/US2011/31681, filed on Apr. 8, 2011,which claims priority to U.S. Provisional Patent Application No.61/322,074 filed on Apr. 8, 2010, the disclosure of which isincorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to synthesis of ¹⁸F-labeled probes forpositron emission tomography (“PET”). More specifically, a method ofsynthesizing ¹⁸F-labeled probes is disclosed, where a solvent with apredetermined amount of water in at least one organic solvent is used toa) elute the ¹⁸F-fluoride from an anion exchange cartridge and b)perform the ¹⁸F-labeling, without drying the ¹⁸F-fluoride, in thepresence of at least one labeling reagent and at least one phasetransfer catalyst.

2. Description of Related Art

Synthesis of ¹⁸F-labeled probes for positron emission tomography (“PET”)has increased tremendously over the last 10 years as there is a growingdemand for radiopharmaceuticals that successfully detect aberrantbiochemical functions in vivo. The unique physiochemical properties ofPET tracers make them ideally suited for several imaging applicationssuch as the early detection and staging of diseases, treatmentmonitoring and stratification of patients who may or may not respond toa particular therapy.

The synthesis of these radiolabeled molecules is undoubtedly timeconsuming, labor intensive and randomly unreliable. In an effort tominimize these production issues, radiochemists have attempted to reducethe labeling procedures to their simplest, quickest and most reliableprotocols. Despite these process improvements, the radiolabelingprocesses still contain inherent inefficiencies that would benefit fromfurther chemistry and process improvements.

The conventional means for ¹⁸F-labeling involves the formation of“activated” or “naked” fluoride, i.e. fluoride that is sufficientlymoisture-free and thus suitable for radiolabeling. It is widely knownthat the desolvation of fluoride increases its nucleophilic character.See V. M. Vlasov, “Fluoride ion as a nucleophile and a leaving group inaromatic nucleophilic substitution reactions”, J. of Fluorine Chem.,vol. 61, pp. 193-216 (1993). In these conventional labeling protocols,trace amounts of ¹⁸F-fluoride are sequestered onto an anion exchangecolumn from several milliliters of ¹⁸O-water. Afterwards, the¹⁸F-fluoride ion is eluted from the anion exchange column through theuse of salts, such as K₂CO₃, dissolved in water. An additive such as thepotassium crown ether Kryptofix K222, which is dissolved in anhydrousacetonitrile, may be used in conjunction with aqueous K₂CO₃ tofacilitate the elution of ¹⁸F-fluoride, or optionally added into thereaction vessel after the K₂CO₃-mediate elution. After the elution step,there is an extensive drying protocol needed as reagents K₂CO₃ andKryptofix K222 are in a highly hydrous solution of acetonitrile. Thisdrying step generates an activated mixture of K₂CO₃, Kryptofix K222 and¹⁸F-fluoride. The drying process begins by evaporating the azeotropicmixture at elevated temperatures, oftentimes at reduced pressures to aidin the evaporation of water from the reaction vessel. This initialdrying can take up to 30 minutes to complete, depending on theefficiency of drying. After the first evaporation, it may be necessaryto perform additional evaporations to effectively remove of enough waterto render the ¹⁸F-fluoride sufficiently moisture-free for labeling.

There are several inherent problems with this approach to generatingactivate reagents for ¹⁸F-fluorination. First, the amount of waterpresent after the initial drying step will vary from run to run givenmechanical differences in vacuum, gas flows, valve integrity andtemperature control. Any single mechanical problem, or combinationthereof, will negatively impact the efficiency of drying and hence, thelabeling results. Since the amount of residual water could vary greatlyfrom run to run, the radiolabeling results would then be inconsistent,making reliable production of radiotracers difficult. Also, given thetime needed to successfully dry the fluoride, a good portion of thetotal synthesis time is dedicated to the drying step. Lastly, because ofthe concern of residual water in the reaction, there is a potential foroperators to “overdry” the reaction mixture prior to fluorination. Inthis instance, drying the reagents for too long may be as equallyhurtful as under-drying the reagents (under-drying being the failure toremove sufficient moisture from the reagents for ¹⁸F-fluorination). Forexample, Kryptofix K222 decomposition is directly related to dryingtimes and temperatures: prolonged drying at high temperature compromisesthe integrity and functionality of Kryptofix K222. To address theseissues, a method that minimizes the length of drying and can accuratelycontrol the amount of moisture from run to run would be a substantialimprovement to current radiolabeling practices.

Alternate methods have been developed in an attempt to obviate the needfor the drying step that either elute ¹⁸F-fluoride from anion exchangeresins using additives in either anhydrous organic solvents (such asacetonitrile, see Joël Aerts et al., “Fast production of highlyconcentrated reactive [¹⁸F] fluoride for aliphatic and aromaticnucleophilic radiolabeling”, Tetrahedron Letters, vol. 51, pp. 64-66(2009); International Patent Application Pub. No. WO 2009/003251) or byusing ionic liquids in hydrous acetonitrile (Hyung Woo Kim et al.,“Rapid synthesis of [¹⁸F]FDG without an evaporation step using an ionicliquid”, Applied Radiation and Isotopes, vol. 61, pp. 1241-1246 (2004)).For these types of elutions using compounds with unknown toxicities, onewould want to assay for these additives in the final product prior toinjection and imaging, which ultimately complicates the productionworkflow.

The use of hydroalcoholic (i.e. protic solvents) co-mixtures is reportedto improve ¹⁸F-labeling yields over the standard single solvent¹⁸F-labeling conditions. Dong Wook Kim et al., “A New Class of S_(N)2Reactions Catalyzed by Protic Solvents: Facile Fluorination for IsotopicLabeling of Diagnostic Molecules”, J. Am. Chem. Soc., vol. 128, no. 50,pp. 16394-16397 (Nov. 23, 2006). While the increases in yields arebelieved to be a result of the unique interactions between the¹⁸F-fluoride and possibly the leaving group on the precursor, it is notpractical to use hydroalcoholic solvents, such as t-amyl alcohol, asthey must be analyzed in the final product. Additionally, the lowpolarity of these bulky solvents can hinder the precursor's solubilitywhich can be used for the labeling reaction, thus negatively impactingthe radiolabeling yield.

SUMMARY OF THE INVENTION

An ideal process for labeling would include an additive that benefitsthe labeling yields, requires no additional testing beyond what iscurrently in place for tracer production, eliminates the need for thedrying step and allows for the precise amount of water to be present ineach reaction for every run.

With this in mind, one embodiment of the current inventions includes amethod for synthesizing an ¹⁸F-labeled probe. The method includes a stepof eluting an amount of ¹⁸F with a first solvent which includes apredetermined amount of water and at least one organic solvent. In thisstep, the ¹⁸F elutes as an ¹⁸F solution. The method also includes a stepof using the ¹⁸F solution to perform ¹⁸F-labeling in the presence of atleast one labeling reagent and at least one phase transfer catalyst soas to generate the ¹⁸F-labeled probe. In the method, there is no step ofdrying the ¹⁸F starting from a time when the eluting step is performedand ending at a time when the ¹⁸F-labeling step is performed.

A solution for use in synthesizing an ¹⁸F-labeled probe is alsoprovided. The solution includes an amount of ¹⁸F, water, and at leastone organic solvent. The total amount of water in this solution is in arange of about 0.1% to about 5.0%. The solution may also include atleast one labeling reagent, and at least one phase transfer catalyst. Inaddition, the solution may include a probe precursor, and have a totalamount of water in a range of about 0.1% to about 2.0%.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an example of fluorodeoxyglucose (¹⁸F) (“FDG” or “¹⁸F-FDG”)synthesis (run number 1) radio thin layer chromatography (“Radio-TLC”)of the crude product after fluorination. Rgn 1 is ¹⁸F-fluoride, Rgn 2 is¹⁸F-FDG, Rgn 3 is an unknown ¹⁸F-labeled by-product, Rgn 4 istetra-acetyl ¹⁸F-FDG;

FIG. 2 shows an example of ¹⁸F-FDG synthesis (run number 2) Radio-TLC ofthe crude product after fluorination. Rgn 1 is ¹⁸F-fluoride, Rgn 2 istetra-acetyl ¹⁸F-FDG;

FIG. 3 shows an example of Radio-TLC of the purified ¹⁸F-FDG as measuredby Radio-TLC. The purity of ¹⁸F-FDG is greater than 98%;

FIG. 4 shows an example of [¹⁸F]-fluorodeoxythymidine (“¹⁸F-FLT”)synthesis, Radio-TLC of the crude product after fluorination. Rgn 1 is¹⁸F-fluoride, Rgn 2 is Bis-Boc ¹⁸F-FLT;

FIG. 5 shows an example of ¹⁸F-FLT synthesis, radio high-pressure liquidchromatography (“Radio-HPLC”) of the crude product after hydrolysis.Peaks 2 and 3 are ¹⁸F-fluoride, Peak 4 is ¹⁸F-FLT;

FIG. 6 shows[¹⁸F]-3-Fluoro-2-(4-((2-nitro-1H-imidazol-1-yl)methyl)-1H-1,2,3-triazol-1-yl)propan-1-ol(“¹⁸F-HX4”) synthesis, Radio-HPLC of the crude product after hydrolysis.Peak 1 is ¹⁸F-fluoride, Peak 2 is a mixture of ¹⁸F-HX4 and¹⁸F-HX4-acetate;

FIG. 7 shows ¹⁸F-HX4 synthesis, Radio-HPLC of the crude product after¹⁸F-fluorination. Peak 1 is ¹⁸F-fluoride, Peak 2 is ¹⁸F-HX4-OAc; and

FIG. 8 shows ¹⁸F-HX4 synthesis, Radio-HPLC of the crude product afterdeprotection. Peak 1 is ¹⁸F-fluoride generated by radiolysis, Peak 2 is¹⁸F-HX4 and Peak 3 is ¹⁸F-HX4-OAc. Peak 1 was not considered incalculating the conversion of ¹⁸F-HX4-OAc into ¹⁸F-HX4.

DETAILED DESCRIPTION OF EMBODIMENTS

It is to be understood that the figures and descriptions of the presentinvention have been simplified to illustrate elements that are relevantfor a clear understanding of the present invention, while eliminating,for purposes of clarity, many other elements which are conventional inthis art. Those of ordinary skill in the art will recognize that otherelements are desirable for implementing the present invention. However,because such elements are well known in the art, and because they do notfacilitate a better understanding of the present invention, a discussionof such elements is not provided herein.

The present invention will now be described in detail on the basis ofexemplary embodiments.

In this invention, ¹⁸F-labeling occurs in high yields with preciselycontrolled amounts of water without the use of a lengthy drying step.More specifically, a solvent of a predetermined amount of water in atleast one organic solvent is used to a) elute the ¹⁸F-fluoride from ananion exchange resin and b) perform the ¹⁸F-labeling, without drying the¹⁸F-fluoride, in the presence of at least one labeling reagent and atleast one phase transfer catalyst. Any suitable labeling reagents andphase transfer catalysts may be used. Examples of appropriate labelingreagents include, K₂CO₃, KHCO₃, Cs₂CO₃, potassium mesylate, potassiumoxylate, and tetrabutylammonium bicarbonate, An example of a suitablephase transfer catalyst includes Kryptofix K222. The organic solvent mayinclude a polar aprotic solvent, such as, for example, acetonitrile,dimethyl sulfoxide (“DMSO”), tetrahydrofuran (“THF”), dimethylformamide(“DMF”), N-methylpyrrolidone (“NMP”), and dioxane, as well as others.The organic solvent may also include a polar protic solvent, such as,for example, tBuOH and t-amyl alcohol, as well as others.

The amount of water as a percentage of the total solvent may range fromabout 0.1% to about 2%. Water, for elution from the anion exchangecartridge however, may range from about 0.1% to about 5%. The amount ofbase (e.g., K₂CO₃) may be about 0.1 to about 50 mg/mL. Because theamount of water is controlled by the elution of fluoride, the percentageof water remains the same from run to run, making the radiochemistrymore consistent. Also, because the fluorination appears to tolerate thepresence of a small range of water, there is no need to dry thefluoride. As a beneficial consequence of eliminating the drying step,the decomposition of temperature-sensitive reagents such as KryptofixK222 and tetrabutylammonium bicarbonate (“TBAB”) are minimized.Additionally, the reactions are completed in a shorter period of time,leading to higher yields and more usable product in-hand. There is lessmechanical wear on the instrument, since a portion of mechanical systemis no longer used for drying. Unlike losses of radioactivity commonlyreported as a consequence of drying ¹⁸F-fluoride, this method would notsuffer from this type of radioactivity loss. Lastly, there are fewerchances of labeling failures due to a consistent amount of water alwayspresent in every reaction.

Examples of ¹⁸F-labeled PET probes that can be generated by the methodof the present invention include, but are not limited to,[¹⁸F]-3-Fluoro-2-(4-((2-nitro-1H-imidazol-1-yl)methyl)-1H-1,2,3-triazol-1-yl)propan-1-ol(“HX4” or “¹⁸F-HX4”), fluorodeoxythymidine (“FLT”),1-[¹⁸F]fluoro-3-(2-nitro-1H-imidazol-1-yl)propan-2-ol (“F-MISO”),[¹⁸F]-fluoroazomycinarabinofuranoside (“FAZA”),5-[3-(¹⁸F)fluoropropyl]-2,3-dimethoxy-N-{[(2S)-1-(prop-2-en-1-yl)pyrrolidin-2-yl]methyl}benzamide(“Fallypride”), 9-(4-[¹⁸F]Fluoro-3-hydroxymethylbutyl)guanine (“FHBG”),9-[(3-[¹⁸F]-fluoro-1-hydroxy-2-propoxy)methyl]guanine (“FHPG”),(¹⁸F)fluoroethyl azide, ¹⁸F-4-fluorobenzaldehyde,¹⁸F-4-fluoroethylbenzoate, ¹⁸F-4-fluoromethyl benzoate, and 7-Methoxy-2(6-[¹⁸F]fluoropyridin-3-yl)imidazo[2,1-b]-8-pyridinothiazole(“¹⁸F-W372”). Other examples of ¹⁸F-labeled PET probes that can begenerated by the method of the present invention include, but are notlimited to,2′-Deoxy-2′-[¹⁸F]fluoro-5-fluoro-1-β-D-arabinofuranosyluracil (“FFAU”),as well as the compounds listed in the table below:

1-[2-(¹⁸F)fluoroethyl] piperidin-3-yl hydroxy(diphenyl)acetate

1-[2-(¹⁸F)fluoroethyl] piperidin-4-yl hydroxy(diphenyl)acetate

[¹⁸F]FEDAA1106 N-(5-Fluoro-2-phenoxyphenyl)- N-(2-[¹⁸F]fluoroethyl-5-methoxybenzyl)acetamide

1-(2-deoxy-2-fluoro-β-D- arabinofuranosyl)-5-[2-(¹⁸F)fluoroethyl]pyrimidine- 2,4(1H,3H)-dione

[¹⁸F]FECNT 2-Carbomethoxy-3-(4- chlorophenyl)-8-(2-[¹⁸F]fluoroethyl)nortropane

[¹⁸F]Fluoroethyl SA4503 1-(2-(4-[18F]-fluoroethoxy-3-methoxyphenyl)ethyl)-4- (3-phenylpropyl)piperazine

5-(2′-(¹⁸F)Fluoroethyl) flumazenil

N-(2-chloro-6- methylphenyl)-2-[(6-{4-[2- (¹⁸F)fluoroethyl]piperazin-1-yl)-2-methylpyrimidin-4- yl)amino]-1,3-thiazole- 5-carboxamide

3-[2-(¹⁸F)fluoroethyl]tyrosine

3-[2-(¹⁸F)fluoroethyl]- O-methyltyrosine

[¹⁸F]FDPN 6-O-(2-[¹⁸F]fluoroethyl)- 6-O-desmethyldiprenorphine

[¹⁸F]VM4-037 ¹⁸F-(S)-3-(4-(2-fluoroethoxy) phenyl)-2-(3-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol- 6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamido) propanoic acid

Without intention of being bound by a particular mechanism or theory,the ¹⁸F-fluoride anion may displace a leaving group, which may include,but is not limited to, tosylates, mesylates, triflates, nosylates,brosylates, trialkylammonium salts, sulfonate esters, halogens andnitro-groups with ¹⁸F-fluoride in solvents containing the presence ofabout 0.1% to about 2.0% water.

In general, the process for generating the ¹⁸F-labeled probe includesloading an amount of ¹⁸F onto an anion exchange cartridge. By anionexchange cartridge, what is meant is any vessel containing anyconvenient anion exchange resin or other material suitable for adsorbing¹⁸F. The ¹⁸F loaded on the anion exchange resin is then prepared forelution. This preparation may include washing the cartridge with anorganic solvent (e.g., anhydrous acetonitrile) and then drying thecartridge (e.g., by passing an inert gas through the cartridge.

Next the ¹⁸F is eluted from the cartridge, for example by passing asolution including water, an organic solvent, a labeling reagent, and aphase transfer catalyst through the cartridge so as to obtain an ¹⁸Fsolution containing ¹⁸F, water, the organic solvent, the labelingreagent, and the phase transfer catalyst. At this point the amount ofwater in the ¹⁸F solution may range from 0.1% to 5.0%. A probe precursoris then combined with the ¹⁸F solution so as to arrive at an¹⁸F-labeling solution which has water in an amount of from 0.1% to 2.0%.This can be accomplished, for example, by diluting either the probeprecursor or the ¹⁸F solution, or both, with an appropriate amount oforganic solvent. Accordingly, it is possible to generate the¹⁸F-labeling solution without any drying of the eluted ¹⁸F solution.

While the ¹⁸F-labeling solution should contain water in an amount offrom 0.1% to 2.0%, it is preferable for the water to be in an amount offrom 0.5% to 1.5%, and more preferable for the water to be in an amountof around 1.0%.

Examples Summary of Labeling Results

H₂O in 0.4 mL % H₂O for % conversion % conversion for QMA MeCN % H₂O(intermediate) (product) QMA elution added total for determineddetermined Entry Tracer elution (vol) (vol) labeling by RadioTLC byRadioTLC 1 FDG 5% 20 uL 1.6 mL 1% >95% NA 2 FDG 5% 20 uL 1.6 mL 1% >95%NA 3 FDG 25% 100 uL  1.6 mL 5%  0% NA 4 FDG 5% 20 uL 1.6 mL 1% NA 60%(isolated yield) 5 FLT 5% 20 uL 1.6 mL 1% >90% >93%** 6 HX4 5% 20 uL 1.6mL 1% >90% NA 7 HX4 5% 20 uL 1.6 mL 1% >90%** >70%** **Denotes analysisperformed by Radio-HPLC

Preparation of the K₂CO₃ and Kryptofix K222 Elution Solvent:

K₂CO₃ (11 mg) was dissolved in water (0.1 mL). Kryptofix K222 (100 mg)was dissolved in acetonitrile (1.9 mL). The solutions were mixed and 0.4mL, or 2×0.2 mL, was used to elute ¹⁸F-fluoride from an anion exchangecartridge.

Loading and Drying of the Anion Exchange Cartridge:

An activated anion exchange cartridge (QMA lite, bicarbonate form), wasloaded with ¹⁸F-fluoride in ¹⁸O-water. The cartridge was then washedwith anhydrous acetonitrile (3×1 mL) to remove residual moisture fromthe cartridge. The cartridge was then further dried by passing an inertgas (such as He) through the cartridge for approximately 30 to 90seconds.

Elution of ¹⁸F-Fluoride from the Anion Exchange Cartridge:

After a solution of ¹⁸F-fluoride (up to 50 mCi per run) in ¹⁸O-water waspassed through the ion-exchange column, a solution of K₂CO₃/KryptofixK222 (0.4 mL or 2×0.2 mL) was passed through the anion exchangecartridge into a dried reaction vessel. An additional portion ofanhydrous acetonitrile (0.6 mL) was added to the reaction vessel. Thisfinal step constitutes the formation of ¹⁸F-fluoride in a hydrousorganic solution that was suitable for radiolabeling.

Synthesis of ¹⁸F-FDG (Entries 1, 2 and 3):

Fluorodeoxyglucose (¹⁸F) (“FDG” or “¹⁸F-FDG”) precursor (mannosetriflate, 50 mg) dissolved in acetonitrile (1.0 mL) was added to thereaction vessel containing the activated ¹⁸F-fluoride. The reaction isheated at 90° C. for 45 seconds. Radio thin layer chromatography(“Radio-TLC”) indicated that the percent conversion of ¹⁸F-fluoride to¹⁸F-FDG tetraacetate plus ¹⁸F-FDG was >95% (FIG. 1). This reactionsequence was repeated a second time and the percent conversion of¹⁸F-fluoride to ¹⁸F-FDG tetraacetate plus ¹⁸F-FDG was >95% (FIG. 2).When the labeling was performed in a solution containing 5% water (Entry3), no labeling was observed.

Synthesis of ¹⁸F-FDG (Entry 4):

FDG precursor (mannose triflate, 50 mg) dissolved in acetonitrile (1.0mL) was added to the reaction vessel containing the activated¹⁸F-fluoride (985 mCi). The reaction is heated at 90° C. for 45 seconds.The MeCN was removed under reduced pressure and heat. HCl (2M, 1 mL) wasadded and the reaction was heated at 100° C. for 480 seconds. The crudereaction mixture was diluted with water and passed through a series ofcartridges (Al2O3, C18, ICH—HCO₃) to afford 445 mCi (60% yield, decaycorrected) 65 minutes after EOB. Radio-TLC indicated that purity of¹⁸F-FDG was >95% (FIG. 3).

Synthesis of ¹⁸F-FLT (Entry 5):

Fluorodeoxythymidine (¹⁸F) (“FLT” or “¹⁸F-FLT”) precursor (Boc-Boc-Nos,18.5±1.5 mg) dissolved in Acetonitrile (1.0 mL) is added to the reactionvessel. The reaction is heated at 135° C. for 3 min. Radio-TLC indicatedthat the percent conversion of ¹⁸F-fluoride to ¹⁸F-Di-Boc FLT was >90%(FIG. 4). The MeCN was removed under reduced pressure and heat. Thecrude material was subjected to deprotection conditions (HCl, 1N, 105°C. for 5 min). HPLC analytical analysis (10% EtOH:water) reveals thepresence of ¹⁸F-FLT with a purity of greater than 96% (FIG. 5).

Synthesis of ¹⁸F-HX4 acetate and ¹⁸F-HX4 (Entries 6 and 7):

[¹⁸F]-3-Fluoro-2-(4-((2-nitro-1H-imidazol-1-yl)methyl)-1H-1,2,3-triazol-1-yl)propan-1-ol(“HX4” of “¹⁸F-HX4”) precursor (18.5±1.5 mg) dissolved in Acetonitrile(1.0 mL) is added to the reaction vessel. The reaction is heated at 110°C. for 10 min. Radio-TLC indicated that the percent conversion of¹⁸F-fluoride to ¹⁸F-HX4 and ¹⁸F-HX4 acetate was >90% (FIG. 6). In asecond run, the reaction was repeated and the labeling efficiency wasmonitored by RadioHPLC. After the fluorination step, >90% of the¹⁸F-fluoride was converted into the labeled intermediate ¹⁸F-HX4-OAc(FIG. 7). The MeCN was removed under reduced pressure and heat. Themixture was further heated with K₂CO₃ (1M) at 100 C for 300 seconds tocomplete the deprotection step. The conversion of ¹⁸F-HX4-OAc into¹⁸F-HX4 was determined to be greater than 70% by radioHPLC (FIG. 8).

While this invention has been described in conjunction with the specificembodiments outlined above, it is evident that many alternatives,modifications, and variations will be apparent to those skilled in theart. Accordingly, the preferred embodiments of the invention as setforth above are intended to be illustrative, not limiting. A variety ofmodifications to the embodiments described will be apparent to thoseskilled in the art from the disclosure provided herein. Thus, thepresent invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Variouschanges may be made without departing from the spirit and scope of theinventions as defined in the following claims.

What is claimed is:
 1. A method for synthesizing an ¹⁸F-labeled probethe method comprising: (1) eluting an amount of ¹⁸F with a first solventcomprising a predetermined amount of water and at least one organicpolar aprotic solvent, but no organic erotic solvents, the ¹⁸F elutingas an ¹⁸F solution, the predetermined amount of water being in a rangeof about 0.1 vol % to about 5.0 vol %; and (2) using the ¹⁸F solution toperform ¹⁸F-labeling in the presence of at least one labeling reagentand at least one phase transfer catalyst so as to generate the¹⁸F-labeled probe; wherein the at least one labeling reagent comprisesK₂CO₃, KHCO₃, Cs₂CO₃, potassium mesylate, potassium oxylate, ortetrabutylammonium bicarbonate; wherein the water content of the ¹⁸Fsolution during ¹⁸F-labeling is in a range of about 0.1 vol % to about2.0 vol %; and wherein there is no step of drying the ¹⁸F solutionstarting from a time when the eluting is performed and ending at a timewhen the ¹⁸F-labeling is performed.
 2. The method of claim 1, whereinthe first solvent further comprises the at least one labeling reagentand the at least one phase transfer catalyst.
 3. The method of claim 1,wherein the ¹⁸F-labeling step includes combining the ¹⁸F solution with aprobe precursor so as to arrive at an ¹⁸F-labeling solution with thetotal amount of water in a range of about 0.1 vol % to about 2.0 vol %.4. The method of claim 3, wherein the ¹⁸F-labeling step further includesdiluting at least one of the ¹⁸F solution and the probe precursor withan organic solvent so that, when the ¹⁸F solution and the probeprecursor are combined, the total amount of water in the ¹⁸F-labelingsolution is in the range of about 0.1 vol % to about 2.0 vol %.
 5. Themethod of claim 1, wherein the at least one phase transfer catalyst isKryptofix K222.
 6. The method of claim 1; wherein the polar aproticsolvent is selected from the group consisting of acetonitrile,tetrahydrofuran (“THF”), dimethylformamide (“DMF”), N methylpyrrolidone(“NMP”), and dioxane.
 7. The method of claim 1, wherein the ¹⁸F-labeledprobe generated is selected from the group consisting of ¹⁸F FDG, ¹⁸FHX4, ¹⁸F FLT, ¹⁸F MISO, ¹⁸F FAZA, ¹⁸F Fallypride, ¹⁸F FHBG, ¹⁸F FHPG,¹⁸F-4-fluorobenzaldehyde, ¹⁸F-4-fluoroethylbenzoate, ¹⁸F-4-fluoromethylbenzoate, ¹⁸F-fluoroethylazide, and ¹⁸F-W372.
 8. The method of claim 1;wherein the ¹⁸F-labeled probe generated is ¹⁸F-VM4-037.
 9. A method forsynthesizing an ¹⁸F-labeled probe the method comprising: (1) eluting anamount of ¹⁸F with a solution comprising: (a) a first solvent comprisinga predetermined amount of water and at least one organic aproticsolvent, but no organic protic solvents; and (b) at least one labelingreagent comprising K₂CO₃, KHCO₃, Cs₂CO₃, potassium mesylate, potassiumoxylate, or tetrabutylammonium bicarbonate; and (c) at least one phasetransfer catalyst; the ¹⁸F eluting as an ¹⁸F solution, wherein a totalamount of water in the ¹⁸F solution is in a range of about 0.1 vol % toabout 5.0 vol %; and (2) diluting the ¹⁸F solution with the organicsolvent so as to provide an ¹⁸F-labeling solution having a total amountof water in the range of about 0.5 vol % to about 1.5 vol %; (3) usingthe ¹⁸F solution to perform ¹⁸F-labeling so as to generate the ¹⁸Flabeled probe; wherein there is no step of drying the ¹⁸F solutionstarting from a time when the eluting is performed and ending at a timewhen the ¹⁸F-labeling is performed.
 10. A method for synthesizing an¹⁸F-labeled probe the method comprising: (1) eluting an amount of ¹⁸Fwith a solution comprising: (a) a first solvent comprising apredetermined amount of water, no organic protic solvents, and at leastone organic aprotic solvent, selected from acetonitrile, tetrahydrofuran(“THF”), dimethylformamide (“DMF”), N methylpyrrolidone (“NMP”), anddioxane; and (b) at least one labeling reagent comprising K₂CO₃, KHCO₃,Cs₂CO₃, potassium mesylate, potassium oxylate, or tetrabutylammoniumbicarbonate; and (c) at least one phase transfer catalyst; the ¹⁸Feluting as an ¹⁸F solution, wherein a total amount of water in the ¹⁸Fsolution is in a range of about 0.1 vol % to about 5.0 vol %; (2)diluting the ¹⁸F solution with the organic solvent so as to provide an¹⁸F-labeling solution having a total amount of water in the range ofabout 0.1 vol % to about 2.0 vol %; (3) using the ¹⁸F solution toperform ¹⁸F-labeling so as to generate the ¹⁸F labeled probe; andwherein there is no step of drying the ¹⁸F starting from a time when theeluting is performed and ending at a time when the ¹⁸F-labeling isperformed.
 11. The method of claim 10, wherein a total amount of waterin the ¹⁸F solution is in a range of about 0.5 vol % to about 1.5 vol %.12. The method of claim 10, wherein the ¹⁸F-labeling further includesdiluting at least one of the ¹⁸F solution and the probe precursor withan organic solvent so that, when the ¹⁸F solution and the probeprecursor are combined, the ¹⁸F-labeling solution has the total amountof water in the range of about 0.1 vol % to about 2.0 vol %.
 13. Themethod of claim 10, wherein the at least one phase transfer catalyst isKryptofix K222.
 14. The method of claim 10, wherein the ¹⁸F-labeledprobe is ¹⁸F FDG, ¹⁸F HX4, ¹⁸F FLT, ¹⁸F MISO, ¹⁸F FAZA, ¹⁸F Fallypride,¹⁸F FHBG, ¹⁸F FHPG, ¹⁸F-4-fluorobenzaldehyde, 18F-4-fluoroethylbenzoate,¹⁸F-4-fluoromethyl benzoate, ¹⁸F-fluoroethylazide, or ¹⁸F-W372.
 15. Themethod of claim 10, wherein the ¹⁸F-labeled probe is ¹⁸F-VM4-037. 16.The method of claim 9, wherein the ¹⁸F-labeled probe is ¹⁸F FDG, ¹⁸FHX4, ¹⁸F FLT, ¹⁸F MISO, ¹⁸F FAZA, ¹⁸F Fallypride, ¹⁸F FHBG, ¹⁸F FHPG,¹⁸F-4-fluorobenzaldehyde, 18F-4-fluoroethylbenzoate, ¹⁸F-4-fluoromethylbenzoate, ¹⁸F-fluoroethylazide, or ¹⁸F-W372.